由于其罕见性，鼻腔鳞状细胞癌（SNSCC）的肿瘤发生机制仍然知之甚少。 SNSCC 的一部分与人乳头瘤病毒 (HPV) 有关；然而，目前尚不清楚 HPV 是否是 HPV 相关 SNSCC 肿瘤发生的驱动因素，或者仅仅是一个中立的旁观者。我们假设，对 SNSCC 进行首次大型高通量测序研究将揭示驱动 HPV 相关和 HPV 独立的 SNSCC 肿瘤发生的分子机制，并确定可靶向的途径。对 64 名 HPV 相关和 HPV 无关鼻鼻癌患者进行了高通量测序。进行了突变注释、病毒整合、拷贝数和基于途径的分析。对 HPV 相关 SNSCC 的分析显示，在 HPV 相关宫颈癌和头颈鳞状细胞癌中观察到类似的突变模式，包括缺乏 TP53 突变以及 PI3K 和 FGFR3 中存在已知的热点突变。进一步的相似之处包括 APOBEC 突变特征的富集、已知热点位置的病毒整合以及表观遗传调节因子的频繁突变。还鉴定了 HPV 相关的 SNSCC 特异性复发突变，包括 KMT2C、UBXN11、AP3S1、MT-ND4 和 MT-ND5。 KMT2D 和 FGFR3 突变与总生存率降低相关。我们开发了第一个已知的 HPV 相关 SNSCC 细胞系，并且对 YAP/TAZ 和 PI3K 途径的组合小分子抑制可协同抑制肿瘤细胞克隆形成。总之，HPV 相关的 SNSCC 和 HPV 独立的 SNSCC 是由不同的分子肿瘤发生机制驱动的。组合阻断 YAP/TAZ 和垂直抑制 PI3K 通路可能有助于靶向 HPV 相关的 SNSCC，而靶向 MYC 和水平抑制 RAS/PI3K 通路则可用于治疗 HPV 独立的 SNSCC。这项研究巩固了 HPV 作为 HPV 相关 SNSCC 的驱动因素。 SNSCC 肿瘤发生，确定区分 HPV 相关和 HPV 独立 SNSCC 的分子机制，并阐明 YAP/TAZ 和 PI3K 阻断作为 HPV 相关 SNSCC 的关键靶点。

Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly described due to its rare nature. A subset of SNSCC are associated with the human papillomavirus (HPV); however, it is unknown whether HPV is a driver of HPV-associated SNSCC tumorigenesis or merely a neutral bystander. We hypothesized that performing the first large high-throughput sequencing study of SNSCC would reveal molecular mechanisms of tumorigenesis driving HPV-associated and HPV-independent SNSCC and identify targetable pathways. High-throughput sequencing was performed on 64 patients with HPV-associated and HPV-independent sinonasal carcinomas. Mutation annotation, viral integration, copy number, and pathway-based analyses were performed. Analysis of HPV-associated SNSCC revealed similar mutational patterns observed in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations and the presence of known hotspot mutations in PI3K and FGFR3. Further similarities included enrichment of APOBEC mutational signature, viral integration at known hotspot locations, and frequent mutations in epigenetic regulators. HPV-associated SNSCC-specific recurrent mutations were also identified including KMT2C , UBXN11 , AP3S1 , MT-ND4 , and MT-ND5 . Mutations in KMT2D and FGFR3 were associated with decreased overall survival. We developed the first known HPV-associated SNSCC cell line and combinatorial small molecule inhibition of YAP/TAZ and PI3K pathways synergistically inhibited tumor cell clonogenicity. In conclusion, HPV-associated SNSCC and HPV-independent SNSCC are driven by molecularly distinct mechanisms of tumorigenesis. Combinatorial blockade of YAP/TAZ and vertical inhibition of the PI3K pathway may be useful in targeting HPV-associated SNSCC whereas targeting MYC and horizontal inhibition of RAS/PI3K pathways for HPV-independent SNSCC.This study solidifies HPV as a driver of HPV-associated SNSCC tumorigenesis, identifies molecular mechanisms distinguishing HPV-associated and HPV-independent SNSCC, and elucidates YAP/TAZ and PI3K blockade as key targets for HPV-associated SNSCC.